Core D: Neuropathology Project Summary Alzheimer disease (AD) is the leading cause of dementia in the world, but many other diseases of the brain can also cause cognitive decline. Unfortunately, these diseases have overlapping clinical signs and symptoms, and they often coexist in older individuals with dementia. These circumstances greatly complicate our overarching mission ?to prevent and treat Alzheimer disease and related dementias by 2025? (the primary objective of the National Plan to Address Alzheimer Disease [NAPA]). To accomplish this mission, we must first: (1) improve our ability to distinguish and diagnose specific individual brain diseases in living participants; and (2) understand the pathophysiological mechanisms through which these diseases develop and lead to dementia. In this effort, studies of postmortem brain tissue are indispensable. Comprehensive brain examination can establish not only whether a person had AD and how advanced that AD pathology had become, but can also detect and measure the severity of other neurodegenerative diseases that can mimic and/or coincide with AD. Just as important, scientific studies of postmortem brain specimens can facilitate the development and testing of new brain scans (neuroimaging biomarker compounds) in ways that are not possible in living participants, and can reveal new secrets about the pathophysiology of AD and related dementias. The mission of the Alzheimer Disease Research Center (ADRC) Neuropathology Core (NPC) is to collect, process, analyze, store, and distribute autopsy brain tissue from study participants to support the Specific Aims of the ADRC and other scientists around the world, as we all strive to prevent and treat AD and related dementias. Towards this end, the NPC examines brains for signs of pathology (including the amounts and distributions of neuronal loss, gliosis, vascular disease sequela, and deposits of abnormal disease-associated proteins [A?, hyperphosphorylated tau, alpha-synuclein, and pTDP-43]). These detailed studies enable us to communicate appropriate diagnoses to the families of participant brain donors, and to supply appropriate data and tissues to scientific collaborators. These collaborations allow the correlation of clinical, neuroimaging, biochemical, and molecular features to neuropathologic features of AD and related dementias.